1. Field of the Invention
The present invention relates to a process for recovering nucleoside derivatives. More particularly, the present invention relates to a process for recovering 3'-azido-3'-deoxythymidine or derivatives thereof directly from the reaction mixture and from the mother liquor remaining from a general process for production thereof.
2. Brief Description of the Prior Art
Nucleoside derivatives having anti-viral activity are known. For example, U.S. Pat. No. 4,211,773 (Lopez et al) discloses pyrimidine nucleosides, specifically, 5-substituted-1-(2'-deoxy-2'-substituted-.beta.-D-arabinofuranosyl) pyrimidine nucleosides which exhibit anti-vital effects. These compounds have the following general formula: ##STR1## wherein A may be, inter alia, an oxyalkyl group; B may be oxygen or sulfur; X may be, inter alia, a halogen; Y may be, inter alia, a halogen or a substituted or non-substituted amino group; Z may be methyne or nitrogen; and each of R.sup.1 and R.sup.2 may be, inter alia, hydrogen.
Further, as disclosed in U.S. Pat. No. 4,904,770, other thymidine derivatives have been reported to possess in vitro activity specifically against the AIDS virus. The compound 2',3'-dideoxy-2',3-didehydrothymidine (d4T) is such a thymidine derivative and has the following general formula: ##STR2## wherein each of X, Y and Z may be, inter alia, nitrogen or C-H and R.sup.4 may be OH or NH.sub.2.
3'-Azido-3'-deoxythymidine, also known commercially as AZT or zidovudine, is one of the most commonly known nucleoside derivatives having activity against the AIDS virus and thus, is useful in treating humans infected with the virus. Pharmaceutically basic salts of AZT as well as 5'-mono-, di- and tri-phosphates of AZT or basic salts thereof (i.e. derivatives thereof) are also useful in treating AIDS. As is well known in the art, zidovudine has the following chemical formula: ##STR3##
Various methods of producing and/or using zidovudine or related compounds such as the pharmaceutically basic salt thereof and the 5'-mono-, di- or tri- phosphate thereof are disclosed in J. Org. Chem. 38, 4299 (1973) (Glinski et al), Nucleosides and Nucleotides, 9, 629 (1990) (Watanabe et al), and in U.S. Pat. No. 4,724,232 (Rideout et al), U.S. Pat. No. 4,818,538 (Rideout et al), U.S. Pat. No. 4,818,750 (Rideout et al), U.S. Pat. No. 4,828,838 (Rideout et al), U.S. Pat. No. 4,833,130 (Rideout et al), U.S. Pat. No. 4,837,208 (Rideout et al), U.S. Pat. No. 4,847,244 (Rideout et al), U.S. Pat. No. 4,857,511 (Rideout et al), U.S. Pat. No. 4,874,609 (Rideout et al), U.S. Pat. No. 4,916,218 (Almond et at), the contents of each of which are hereby incorporated by reference.
Large scale manufacture of zidovudine based on one or more of the methods of production referred in the previous paragraph is known. The resultant crude crystalline zidovudine can be recrystallized to pharmaceutically acceptable purity (i.e. purity greater than 99.5%) by conventional techniques. Unfortunately, while these techniques may be useful to reduce the levels of impurities, they require multiple recrystallization steps and thus the efficiency of the recovery of pharmaceutical grade zidovudine is significantly less than theoretical, typically from about 30 to about 60 percent at most. For example, Glinski et al (see above) report a yield of only about 30 percent of theoretical. Since the cost of producing zidovudine can easily exceed US$5000/kg, any yield of the final product (e.g. in pharmaceutically pure form) significantly less than theoretical is indicative of a relatively inefficient process. In light of this, it would be desirable to have an improved process for recovery of zidovudine or derivatives which results in an overall improved yield of the final product.